Resistance of bacteria to conventional antibiotics used to treat human disease has risen to an international crisis level. A contributing factor has been the widespread use of antibiotics to treat non-life-threatening infections. In recent years, there has been much focus on a promising new class of bacteriocins known as lantibiotics. At present, lantibiotics are being used extensively by the food industry. Lantibiotics have significant commercial value and broad applicability, and practical methods for their production would have a significant economic impact.
Lantibiotics are antimicrobial proteins produced by bacteria that display growth-inhibitory activity against a range of related bacteria. Lantibiotics are polypeptide antimicrobial agents that are produced by certain bacteria and are distinguishable from other antibiotics because of their polypeptide nature and bioactive properties. For example, nisin, a lysine-rich lantibiotic used as a preservative for certain foods, has the unusual amino acid residues lanthionine and β-methyl-lanthionine. Nisin is non-toxic to humans and animals, is resistant to high temperatures, and is bacteriostatic at very low concentrations. Unfortunately, although lantibiotics are versatile and have unique and advantageous properties, the lack of commercially viable methods for production and isolation at high purity has limited their utility.
Recently, the potential value of nisin for the milk industry has been recognized, in particular, in connection with the ability of nisin to help fight mastitis infection in cows. The advantage offered by nisin stems, in large part, from its potential to reduce or eliminate “withhold period” rules. The withhold period is a time established, during treatment of mastitis infection of cows, when milk from the infected cow must be discarded. Thus, milk from cows treated with nisin for mastitis infection can enter the fluid milk stream immediately compared to traditional antibiotic treatment.
Unfortunately, nisin that is commercially produced by currently available methods of production and purification is considered food grade quality and is not of sufficient purity for pharmaceutical applications. Currently available methods use media comprising whey protein concentrate (WPC) during fermentation of lantibiotic-producing microorganisms to produce lantibiotics. However, the concentrations of WPC necessary for efficient production of lantibiotics using methods normally used to prepare lantibiotics lead to the production of drug substance impurities. Therefore, due to the lack of efficient alternative methods of production and purification which could produce nisin free of such impurities, the value derived from treatment of mastitis with nisin is insufficient to counterbalance current practices.
There is a long-felt need for improved, cost-effective, commercially-viable, culture methods for lantibiotic production without also producing contaminating high levels of WPC-related impurities in the initial preparation. Such culture methods can yield lantibiotics having high purity suitable for pharmaceutical use.